H.-J. Möller

Comparative Efficacy of Antidepressants

SummarySelective serotonin reuptake inhibitors (SSRIs) are a recently developed class of drugs with significantly greater antidepressant efficacy than placebo. Generally, in double-blind comparative trials, all SSRIs demonstrated antidepressant efficacy similar to that of the ‘standard’ tricyclic antidepressants amitriptyline and imipramine; a meta-analysis of controlled trials found the efficacy of the SSRIs to be equivalent to that of the 2 tricyclics. Nevertheless, because of small patient numbers included in most studies that compare SSRIs with other antidepressants, no definitive statements about relative efficacy can be made. In these studies it is simply possible to state that no statistically significant differences were identified between SSRIs and the comparative antidepressants. Importantly, differences in clinical characteristics exist between the SSRIs — differences in elimination half-life (t½β) between fluoxetine and/or its metabolite (total t½β = 330 hours) and other SSRIs (t½β range = 15 to 30 hours), for example. This has implications in terms of potential drug interactions and must be considered when patients have to be switched to treatment with monoamine oxidase inhibitors.Studies with fluvoxamine have been conducted in both in- and outpatients, whereas trials with other SSRIs have been confined largely to outpatient populations. Fluvoxamine has been associated with a high incidence of nausea (37%), although this may have resulted from high initial dosages (rather than upward dose titration protocols) used in early trials. Of further interest, fluoxetine doses of 20mg may be sufficient to produce a satisfactory antidepressant response, and this SSRI may be particularly useful in patients with chronic retarded depression. More clinical data are required before the efficacy of sertraline and citalopram relative to standard antidepressants can be clearly defined. Preliminary data indicate that SSRIs are effective in the treatment of panic disorder, obsessive-compulsive disorder (OCD), eating (e.g. anorexia and bulimia) and personality disorders (e.g. anger, impulsiveness) and substance abuse (e.g. alcoholism); early results with fluvoxamine in the treatment of panic disorder and OCD, and with fluoxetine in the treatment of bulimia, personality disorders and alcohol abuse, have been encouraging.SSRIs have a more favourable tolerability profile than tricyclic antidepressants and, unlike the tricyclics, are not associated with anticholinergic adverse effects, sedation, cardiotoxicity or weight gain. SSRIs are associated with a relatively high incidence of nausea, particularly if high doses are used at the start of treatment. However, the incidence of nausea appears to decrease as treatment is continued. Although SSRIs appear to be well tolerated, they are a new drug class and, thus, patients should be monitored carefully for the occurrence of unexpected adverse reactions (e.g. the ‘flu-like’ illness noted in a small number of zimeldine recipients).Overall, SSRIs have been shown to be effective and safe agents for the treatment of patients with major depressive disorders. These drugs possess tolerability advantages over tricyclic antidepressants, and preliminary evidence suggests that they may have future value in the treatment of panic disorder, OCD, eating and personality disorders, and substance abuse.

A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolar mania.

The aim of this study was to evaluate the efficacy and tolerability of quetiapine combined with lithium or divalproex in the treatment of bipolar mania. Patients were randomized to 6 weeks of quetiapine (up to 800u2009mg/day) and lithium/divalproex (Li/DVP) (target trough serum concentrations of 0.7–1.0u2009mEq/L and 50–100u2009μg/mL, respectively) or placebo and lithium/divalproex. Quetiapine+lithium/divalproex treatment (n=104) showed a 2.0-point greater improvement on the primary outcome (change from baseline in Young Mania Rating Scale total score at day 21) compared with placebo+lithium/divalproex (n=96), and a 2.8-point greater difference by day 42, but the differences between groups were not statistically significant. Other efficacy measures, however, did show a statistically significant advantage in favor of quetiapine+lithium/divalproex over lithium/divalproex monotherapy at day 42. Improvement of mean Young Mania Rating Scale scores with quetiapine+lithium/divalproex was numerically but not statistically significantly greater than lithium/divalproex monotherapy in the treatment of bipolar mania. Potential reasons for the failure of quetiapine+lithium/divalproex to differentiate from placebo+lithium/divalproex treatment on the primary outcome measure and the implications of this for the treatment of mania and future studies are discussed. Overall, the combination of quetiapine with lithium or divalproex was well tolerated.

Recurrent brief depression and its relationship to seasonal affective disorder

SummaryRecurrent brief depression (RBD) and seasonal affective disorder (SAD) have been both recently described as subgroups of major depression (DSM-III-R). We have established a relationship between these two syndromes in a cohort of 42 outpatients who presented themselfes to a clinic for seasonal affective disorder at the Psychiatric Department of the University of Bonn, FRG. Our preliminary data indicate that 31% of the patients who were diagnosed as suffering from either SAD or its subsyndromal form (S-SAD) can also be categorized as RBD (RBD-seasonal) in a 1-year observation period. During the time span of 1 year RBD-seasonal patients had a mean number of 20 (SD 9) episodes compared with 6 (SD 5) episodes (P<0.001) in the group of seasonal patients without BRD. These episodes were accentuated in fall/winter and outnumbered those in spring/summer significantly (P<0.001). The mean duration of each episode was 4.6 (SD 2.6) days in the RBD-seasonal group and 21.8 (SD 29) in the non-RBD-seasonal group. Patients with RBD-seasonal experienced seasonal changes as more of a problem and reported a lower percentage of first-degree relatives with a history of depression than the non-RBD-seasonal group.

Brofaromine in elderly major depressed patients--a comparative trial versus imipramine.

In an 8-week controlled double-blind clinical trial with a total of 189 elderly patients brofaromine showed comparable efficacy to imipramine (Hamilton Depression Scale, von Zerssen self-rating scale, global evaluation). The numbers of adverse events were the same in both groups, but the spectrum differed distinctly. In the global evaluation of tolerability, there was an advantage for brofaromine. Mean daily doses were 85 mg/day in the brofaromine group and 87 mg/day in the imipramine group. Long-term efficacy and tolerability also proved to be good in the open follow-up of the patients treated with brofaromine.

Are serotonergic reuptake inhibitors more potent in reducing suicidality? An empirical study on paroxetine

There is some empirical evidence that selective serotonin reuptake inhibitors reduce suicidal ideas faster than other antidepressants. These findings are well in line with the theory of a serotonergic hypofunction in suicidal patients. To test this hypothesis the data of a 6-week double-blind control-group study comparing paroxetine versus amitriptyline were analyzed with respect to suicidality. The global antidepressive efficacy was comparable under dosages of 30 mg paroxetine or 150 mg amitriptyline per day. A differentiated analysis failed to confirm the hypothesis of a faster reduction of suicidal cognitions by paroxetine.

Prediction of short-term outcome of neurotic-depressive inpatients. Results of an empirical study of 134 inpatients.

SummaryA study was carried out involving 134 neurotic-depressive inpatients (according to ICD-9) treated with cognitive behaviour therapy and in a subgroup additionally with antidepressants. Using standardized rating instruments, a large set of potential predictor variables was tested. After cross-validation according to the splithalf technique, only very few of these proved to be suitable as predictors for the main outcome criteria. These predictors included certain aspects of social functioning before index admission, intensity of depressive symptoms at admission and the degree of self-evaluated mood disturbances three weeks after admission. Several predictors known from the literature could not be reproduced in this study, demonstrating the well-known instability of most predictor findings. On the other side, the predictor profile of the neurotic-depressive patients was quite similar to that found in endogenous depressives, a result which might — together with other findings, such as the response of neurotic depressives to antidepressants — question the traditional subclassification of functional depressive states into these subgroups.

Outcome-Forschung als Mittel der Qualitätssicherung

Mit der zunehmenden Forderung nach Masnahmen der Qualitatssicherung wird eine ausreichende Therapieeffizienzkontrolle im Sinne einer Outcome-Forschung eine unabweisbare Notwendigkeit. Der Umfang der prinzipiell im Rahmen einer dezidierten Outcome-Forschung zu erhebenden Variablen mus dabei unter Praktikabilitatsaspekten an den jeweiligen Versorgungsbereich und die jeweilige Fragestellung angepast werden.

Erniedrigter Serotonin-Turnover ist bei suizidalen depressiven und schizophrenen Patienten von einer kompensatorischen Up-Regulation des Serotonin2-Rezeptors begleitet

Bei suizidalen Patienten ist der Serotonin-(5HT)-Turnover erniedrigt und manifestiert sich als verringerte Konzentration der 5-Hydroxyindol-Essigsaure im Liquor (Asberg et al. 1976). Bei Suizidopfern wird weiterhin prasynaptisch die Reduktion der maximalen Bindung (Bmax) des 5HT-Transporters sowie postsynaptisch eine Erhohung der Bmax des 5HT2-Rezeptors im frontalen Cortex beobachtet (Mann et al. 1986). Diese Erniedrigung des 5HT-Turnovers wird nicht nur zentral, sondern auch peripher als erniedrigte Blut-5HT-Konzentration registriert (Mann et al. 1992, Braunig et al. 1989, Rao et al. 1994). Bei gesunden Probanden reguliert die endogene 5HT-Konzentration im Blut bzw. Thrombozyten kompensatorisch die Affinitat des thrombozytaren 5HT-Transporters und die Bmax des 5HT2-Rezeptors (Meyer-Lindenberg und Rao 1993, Andres et al. 1993). Anhand der vorliegenden Studie sollte die Frage beantwortet werden, ob die bei suizidalen Patienten beobachtete Erniedrigung des Blut-5HTs zu einer kompensatorischen Up-Regulation des 5HT2-Rezeptors auf Thrombozyten fuhrt.

„Frontale Hypoperfusion“ mittels SPECT bei schizophrener Minussymptomatik

In den letzten Jahren wurden deutliche Fortschritte in der Entwicklung und Anwendung bildgebender Verfahren bei neuropsychiatrischen Krankheitsbildern gemacht [1–3]. Neben den die Hirnstruktur mit hoher raumlicher Auflosung darstellenden Verfahren der Transmissions-Computertomographie und der Magnetresonanz Tomographie wird durch Verfahren wie die Positronen-Emissions-Tomographie (PET) und Einzel-Photonen-Emissions-Tomographie (SPECT) die Darstellung von Funktionsstorungen des Gehirns ermoglicht [2]. Bei zahlreichen neuropsychiatrischen Krankheitsbildern wie auch bei der im Rahmen dieser Darstellung interessierenden Schizophrenie sind morphologisch-strukturelle Veranderungen des Gehirns eher subtil und die Interpretation dieser Veranderungen ist im Einzelfall durch grose Uberlappungen zu gesunden Kontrollgruppen zusatzlich erschwert. Auch ist nicht zu erwarten, das sich bei einem schizophrenen Patienten mit akuter psychotischer Symptomatik ein anderer morphologischer Befund zeigt als in der Remissionsphase.

Psychiatrische Diagnostik und Psychopathologie bei HMPAO-SPECT

Mittels bildgebender Verfahren wie die Single-Photon-Ernission-Computed-Tomography (SPECT) und die Positron-Emission-Tomography (PET) konnten bei psychiatrischen Erkrankungen Perfusionsstorungen verschiedener Hirnareale nachgewiesen werden. Bei Schizophrenien hatte man in den fruheren Studien Veranderungen im Frontallappen (Buchsbaum et al. 1982) gefunden. Diese Befunde konnten in den neueren Arbeiten nicht repliziert werden, hingegen scheint der Temporallappen besonders betroffen zu sein (Buchsbaum et al. 1990, deLisi et al. 1989) Bei affektiven Storungen sind Veranderungen im prefrontalen Cortex (Baxter et al. 1989, Cohen et al. 1989) und im Temporallappen (Post et al. 1987, Amsterdam et al. 1992) festgestellt worden. Bei den meisten der obengenannten Untersuchungen — besonders den PET-Studien — wurde meistens die Psychopathologie zum Zeitpunkt der Untersuchung vernachlassigt. Daher haben wir uns im Rahmen des jetzigen Projektes zum Ziel gesetzt, zu untersuchen, inwiefern eine spezifische bzw. globale Psychopathologie im Zusammenhang mit Durchblutungsverhaltnissen (gemessen mit der HMPAO-SPECT-Technik) steht.